Infection-induced inflammatory reactions involve a strong increase in dendritic cells (DCs) at the infection site and draining lymph nodes (dLNs). Whether inflammatory DCs are recruited to these locations or differentiate locally, and what their functional relevance is, remain unclear. Here we showed that during Leishmania infection, monocytes were recruited to the dermis and differentiated into "dermal monocyte-derived DCs," which subsequently migrated into the dLNs. In addition, monocyte recruitment to the dLNs resulted in the differentiation into "LN monocyte-derived DCs." Analysis of the kinetics of monocyte differentiation into DCs, susceptibility to infection, IL-12 production, and L. major-specific T cell stimulation potential suggest that dermal monocyte-derived DCs controlled the induction of protective T helper 1 responses against Leishmania. Thus, the demonstration of monocyte differentiation potential into DCs during in vivo infection and of local DC differentiation in inflammatory foci suggests that de novo formed monocyte-derived DCs are essential in T cell immunity against pathogens.

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SUMMARY Interleukin 2 (IL-2) promotes Foxp3+-regulatory T (Treg) cell responses, but inhibits T follicular helper (TFH) cell development. However, it is not clear how IL-2 affects T follicular regulatory (TFR) cells, a cell type with properties of both Treg and TFH cells. Using an influenza infection model, we demonstrated that high IL-2 concentrations at the peak of the infection prevented TFR cell development by a Blimp-1–dependent mechanism. However, once the immune response resolved, some Treg cells down-regulated CD25, up-regulated Bcl-6 and differentiated into TFR cells, which then migrated into the B cell follicles to prevent the expansion of self-reactive B cell clones. Thus, unlike its effects on conventional Treg cells, IL-2 inhibits TFR cell responses.

The question of which dendritic cells (DCs) respond to pulmonary antigens and cross-prime CD8+ T cells remains controversial. We show that influenza-specific CD8+ T cell priming is controlled by different DCs at different times after infection. Whereas early priming is controlled by both CD103+CD11blo and CD103-CD11bhi DCs, CD103-CD11bhi DCs dominate antigen presentation at the peak of infection. Moreover, CD103-CD11bhi DCs capture exogenous antigens in the lung and directly cross-prime CD8+ T cells in the draining lymph node without transferring antigen to CD8α+ DCs. Finally, we show that CD103-CD11bhi DCs are the only DCs to express CD70 after influenza infection and that CD70 expression on CD103-CD11bhi DCs licenses them to expand CD8+ T cells responding to both influenza and exogenous ovalbumin.

Although cognate encounters between CCR7-expressing antigen-bearing dendritic cells (DCs) and CCR7+ naïve T cells take place within the T cell zone of lymph nodes, it is unknown whether co-localization of the DCs and T cells within the T cell area is obligate for effector generation. Here, we show that, following nematode infection, antigen-bearing DCs and CD4+ T cells upregulate CXCR5 and co-localize in a CXCL13, B cell and lymphotoxin-dependent fashion outside of the T zone. Importantly, lymphotoxin-expressing B cells, CXCL13 and CXCR5-expressing DCs and T cells are also necessary for development of interleukin 4 (IL-4) producing TH2 cells, suggesting that TH2 differentiation can initiate outside of the T cell zone.

SUMMARY Exposure to environmental antigens, such as house dust mite (HDM), often leads to T helper-2 (Th2) cell-driven allergic responses. However, the mechanisms underlying the development of these responses are incompletely understood. We found that the initial exposure to HDM did not lead to Th2 cell development but instead promoted the formation of IL-4-committed T follicular helper (Tfh) cells. Following challenge exposure to HDM, Tfh cells differentiated into interleukin-4 (IL-4) and IL-13 double-producing Th2 cells that accumulated in the lung and recruited eosinophils. B cells were required to expand IL-4-committed Tfh cells during the sensitization phase, but did not directly contribute to disease. Impairment of Tfh responses during the sensitization phase or Tfh cell depletion prevented Th2 cell-mediated responses following challenge. Thus, our data demonstrate that Tfh cells are precursors of HDM-specific Th2 cells and reveal an unexpected role of B cells and Tfh cells in the pathogenesis of allergic asthma.

SummaryHere we test the role of FoxP3+ regulatory T cells (Tregs) in controlling T follicular helper (Tfh) and germinal-center (GC) B cell responses to influenza. In contrast to the idea that Tregs suppress T cell responses, we find that Treg depletion severely reduces the Tfh cell response to influenza virus. Furthermore, Treg depletion prevents the accumulation of influenza-specific GCs. These effects are not due to alterations in TGFβ availability or a precursor-progeny relationship between Tregs and Tfh cells, but are instead mediated by increased availability of IL-2, which suppresses the differentiation of Tfh cells and as a consequence, compromises the GC B response. Thus, Tregs promote influenza-specific GC responses by preventing excessive IL-2 signaling, which suppresses Tfh cell differentiation.

Monocytes have been classically considered essential elements in relation with innate immune responses against pathogens, and inflammatory processes caused by external aggressions, infection and autoimmune disease. However, although their potential to differentiate into dendritic cells (DCs) was discovered 14 years ago, their functional relevance with regard to adaptive immune responses has only been uncovered very recently. Studies performed over the last years have revealed that monocyte-derived DCs play an important role in innate and adaptive immunity, due to their microbicidal potential, capacity to stimulate CD4 + and CD8 + T-cell responses and ability to regulate Immunoglobulin production by B cells. In addition, monocyte-derived DCs not only constitute a subset of DCs formed at inflammatory foci, as previously thought, but also comprise different subsets of DCs located in antigen capture areas, such as the skin and the intestinal, respiratory and reproductive tracts. Monocytes develop in the bone marrow and enter the blood stream until they are recruited to extravascular compartments not only during inflammatory processes but also under steady-state conditions, to maintain the homeostasis of the monocytic cell system. Monocytes were originally described as key elements of the mononuclear phagocytic system, due to their capacity to differentiate into different subsets of tissue macrophages with specific functions. 1 More recently, monocytes have been demonstrated to be endowed also with the potential to differentiate into dendritic cells (DCs) in vivo during inflammation. 2 This discovery has led to the concept that monocyte-derived DCs differentiated locally in inflammatory foci could play an important role with regard to the induction and regulation of immune responses against pathogens and the development of inflammatory and autoimmune diseases. However, so far only a few reports have addressed specifically the role of monocyte-derived DCs in innate and adaptive immunity that nevertheless has become recently an active research area. These studies, carried out over the last few years, have revealed that monocyte-derived DCs have the capacity to induce Th1-polarized CD4 + T-cell responses, 3 crossprime antigen-specific CD8 + T cells 4 exert a microbicidal action by producing tumour-necrosis factor-a (TNF-a) and iNOS, 5 and regulate IgA production by B cells. 6 Monocyte-derived DCs have been considered to constitute an independent category of DCs arising during inflammatory processes, with no role in the generation of DCs in noninflammatory conditions. 7 However, recent studies have revealed that monocytes are the precursors for some important DC subsets found in the steady state, such as Langerhans cells 8 and DC subsets present in the intestinal and respiratory mucosas. 9,10 Because of the lack of relevant information on the role of human monocytes in T-cell responses, this review will be focused on the available information on the role played by mouse monocyte-derived DCs in innate and adaptive immune ...